Hepatitis C virus (HCV) is an important cause of chronic liver disease, cirrhosis and hepatocellular carcinoma in most parts of the world. Its fastidious nature and limited host range have made it difficult to study. In this program, four separate groups of investigators join forces to attack the hepatitis C virus from a variety of different but interrelated vantage points. The four groups (PIs H. Greenberg, C. Rise, T. Wright, and M. Kay) have a well-documented history of collaborations in the general areas of hepatitis viruses and bring a pathogenesis and immunity and will range from clinically based investigation to fundamental analysis of the interaction of the HCV genome and the host. By combining resources, reagents and ideas, the program team hopes to advance the state of knowledge concerning HCV pathogenesis. The individual projects in this program are briefly outlined. Dr. Greenberg who is the overall program director, will carry out studies on the class I restricted CD8+ T cell response to HCV in patients with acute and chronic hepatitis and in patients undergoing liver transplant. He will take advantage of several new assay systems (tetramers and intracellular cytokines) to study responses in peripheral blood and the liver and will work closely with Drs. Wright and Kay to carry out these studies. Dr. Wright will continue her longitudinal analysis of two groups of patients: examine the contributions of virologic and immunologic variables to disease progression and will work collaboratively with Drs. Greenberg and Rice to study host immune responses and hepatocyte response to HCV infection. Dr. Kay will continue to develop his murine model for HCV replication. This model involves the engraftment of human hepatocytes on immunodeficient mice treated with antibody to c-met. Once established, Drs. Kay and Wright to study HCV strain variation phenotypes in the grafts. Finally, Dr. Rice will collaborate with Dr. Greenberg to study hepatocytes and other liver cell transcriptional responses to HCV using microarray techniques. These studies will involve cells in culture which express HCV proteins under the control of an inducible promoter, hepatocytes in vivo derived from chimpanzees and humans, and, when feasible, infected hepatocytes engrafted in our mouse model.